silica dust, crystalline, in the form of quartz or cristobalite - IARC ...

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IARC MONOGRAPHS – 100C Table 3.1 Studies of cancer in experimental animals exposed to crystalline silica (inhalation exposure) Species, strain (sex) Duration Reference Mouse, BALB/c BYJ (F) 150, 300 or 570 d Wilson et al. (1986) Rat, F344 (M, F) 24 mo Dagle et al. (1986) Rat, F344 (F) Lifespan Holland et al. (1983, 1986); Johnson et al. (1987) Rat, SPF F344 (M, F) 30 mo Muhle et al. (1989, 1991, 1995) Rat, Wistar (F) Up to 35 mo Spiethoff et al. (1992) Dosing regimen Animals/group at start Particle size, GSD 0, 1.5, 1.8 or 2.0 mg/m 3 8 h/d, 5 d/wk 6–16 animals Diameter < 2.1 μm 0, 52 mg/m 3 6 h/d, 5 d/wk 72/sex MMAD, 1.7–2.5 μm; GSD, 1.9–2.1 0, 12 mg/m 3 6 h/d, 5 d/wk for 83 wk 62 animals MMAD, 2.24 μm; GSD, 1.75 0, 1 mg/m 3 6 h/d, 5 d/wk for 24 mo 50/sex MMAD, 1.3 μm; GSD, 1.8 0, 6.1, 30.6 mg/m 3 6 h/d, 5 d/wk for 29 d 90 animals MMAD, 1.8 μm; GSD, 2.0 Incidence of tumours in respiratory tract Significance Comments Lung (adenomas): 7/59 (control), 9/60 (all exposed) Lung (epidermoid carcinomas): M–0/42 (control), 1/47 F–0/47 (control), 10/53 Lung (tumours): 0/54 (control), 18/60 (11 adenocarcinomas, 3 squamous cell carcinomas, 6 adenomas) Lung (tumours): 3/100 (control M, F), 7/50 (M), 12/50 (F) M–1 adenoma, 3 adenocarcinomas, 2 benign cystic keratinizing squamous cell tumours, 1 adenosquamous carcinoma, 1 squamous cell carcinoma F–2 adenomas, 8 adenocarcinomas, 2 benign cystic keratinizing squamous cell tumours 0/85 (control), 37/82 (low dose), 43/82 (high dose) Multiple tumours/rat: 21 bronchiolo-alveolar adenomas, 43 bronchiolo-alveolar carcinomas, 67 squamous cell carcinomas, 1 anaplastic carcinoma [NS] [NS] [P < 0.002] [P < 0.001] Nose-only inhalation exposure. Age unspecified Unspecified (M) [P < 0.05] (F) [P < 0.0001] (both doses) Nose-only inhalation exposure d, day or days; F, female; GSD, geometric standard deviation; h, hour or hours; M, male; MMAD, mass median aerodynamic diameter; mo, month or months; NS, not significant; wk, week or weeks 380
Silica dust, crystalline (quartz or crystobalite) 3.2 Intranasal administration 3.2.1 Mouse Two groups of 40 female (C57xBALB/c) F 1 mice received a single intranasal instillation of 4 mg of synthetic d- or l-quartz. A group of 60 females received an intranasal instillation of saline. Survivors were killed at 18 months after treatment, and the incidence of lymphomas and leukaemias combined was 0/60 (controls), 2/40 (d-quartz), and 6/40 (l-quartz) (Ebbesen, 1991). [The Working Group noted that the study was not designed to detect silica-induced lung tumours, and also noted the lack of information on quartz retention.] 3.3 Intratracheal administration See Table 3.2 3.3.1 Mouse A group of 30 male A/J mice, 11–13 weeks old, received weekly intratracheal instillations of 2.9 mg quartz for 15 weeks. A group of 20 mice received instillations of vehicle [unspecified]. Animals were killed 20 weeks after the instillations. The incidences of lung adenomas were 9/29 in the controls, and 4/20 for the silica-instilled mice, values that were not statistically different (McNeill et al., 1990). Ishihara et al. (2002) administered a single dose (2 mg in saline/mouse) of crystalline silica to a group of four C57BL/6N mice by intratracheal instillation to study subsequent genotoxic effects. A control group of four animals was instilled saline only. Silicotic lesions were observed in the lungs of the exposed mice, but no pulmonary neoplasms were observed after 15 months. 3.3.2 Rat A group of 40 Sprague Dawley rats [sex unspecified] received weekly instillations of 7 mg quartz (Min-U-Sil) in saline for 10 weeks. Another groups of 40 rats received instillations of saline alone, and 20 rats remained untreated. Animals were observed over their lifespan. The incidence of lung tumours in quartz-treated rats was 6/36, 0/40 in the saline controls, and 0/18 in the untreated rats (Holland et al., 1983). Groups of 85 male F344 rats received a single intratracheal instillation of 20 mg quartz in deionized water, Min-U-Sil or novaculite, into the left lung. Controls were instilled with vehicle only. Interim sacrifices of ten rats were made at 6, 12, and 18 months with a final sacrifice at 22 months. The incidence of lung tumours in the Min-U-Silinstilled rats was 30/67, in the novaculite-treated rats 21/72, and in controls 1/75. All of the lung tumours were adenocarcinomas, except for one epidermoid carcinoma in the novaculite-treated rats (Groth et al., 1986). Groups of male and female F344/NCr rats [initial number unspecified] received one intratracheal instillation of 12 or 20 mg quartz in saline or 20 mg of ferric oxide (non-fibrogenic dust) in saline. Interim sacrifices were made at 11 and 17 months with a final sacrifice at 26 months. There was a group of untreated controls observed at unscheduled deaths after 17 months. No lung tumours were observed in the ferric-oxidetreated rats and only one adenoma was observed in the untreated controls. The high incidences of benign and mainly malignant lung tumours observed in the quartz-treated rats is summarized in Table 3.3 (Saffiotti, 1990, 1992; Saffiotti et al., 1996). Six groups of 37–50 female Wistar rats, 15 weeks old, received either a single or 15 weekly intratracheal instillation of one of three types of quartz preparations in saline (see Table 3.4). A control group received 15 weekly instillations of saline. To retard the development of silicosis, 381
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